Parkinson's disease (PD) is a chronic neurodegenerative disorder, in which them is extensive degeneration of nigrostriatal dopaminergic neurons. Maintaining the heath of these cells using powerful neurotrophic factors has proven effective in a number of rodent and primate models of PD. The ultimate goal of this proposal is to develop novel high-capacity adenoviral systems for long-term, stable, non-cytotoxie, and non-immunogenic delivery of neurorestorative genes to the brain for the future treatment of chronic neurodegenerative diseases such as PD. Adenovirus-derived vectors serve as efficient gene transfer vehicles in the setting of the CNS. However, use of conventional adenoviral vectors has been limited due to diminished duration of transgene expression as a result of strong anti-viral immune and inflammatory responses that are elicited. Decreased vector-directed transcriptional activity typically leads investigators to administer higher vector doses that ultimately results in enhanced in vivo toxicity. In this proposal, we will utilize the novel design of helper-dependent, high-capacity adenoviral vectors for efficient, safe, and long-term transgene delivery to the brain for the treatment of PD. Specifically, high-capacity helper-dependent adenoviral vectors will be constructed and assessed in vivo. We will monitor their effectiveness and potential inflammatory and immune side effects in detail. We will also test the efficacy of the new vectors to express the potentially neurorestorative gene, glial cell line derived neurotrophic factor (GDNF), and evaluated its capacity to protect dopaminergic neurons in a rodent neurotoxic model of neurodegeneration. The reagents and principles established by this work will be of substantial value to the implementation of novel therapeutics for PD, facilitate the development of tools needed to achieve long-lived, safe, non-cytotoxic transgene expression, and may lead to the development of novel treatments for other chronic neurodegenerative diseases.